The present invention relates to methods for contrast-enhanced imaging of sexual response. In particular, the present invention relates to methods of magnetic resonance imaging (MRI), computerized X-ray tomography (CT), ultrasound, and optical imaging using contrast agents to measure blood flow during sexual response, especially female sexual response. The invention relates to methods of analyzing normal sexual function and sexual dysfunction and provides a means for evaluating and screening potential therapeutic compounds for enhancing sexual function or treating sexual dysfunction.
Diagnostic imaging techniques, such as magnetic resonance imaging (MRI), X-ray, nuclear radiopharmaceutical imaging including PET and SPECT, ultraviolet/visible/infrared light, and ultrasound, have been used in medical diagnosis for a number of years. In some cases, contrast media improves the image quality or provides specific additional useful information.
The contrast agent must interfere with the wavelength of electromagnetic radiation used in the imaging technique, alter the physical properties of tissue to yield an altered signal, or, as in the case of radiopharmaceuticals, provide the source of radiation itself. Commonly used imaging materials include organic molecules, metal ions, salts or chelates, particles (particularly iron particles), or labeled peptides, proteins, polymers or liposomes. After administration, the agent may non-specifically diffuse throughout body compartments prior to being metabolized and/or excreted; these agents are generally known as non-specific agents. Alternatively, the agent may have a specific affinity for a particular body compartment, cell, organ, or tissue; these agents can be referred to as targeted agents.
In recent years, a number of contrast agents have been developed that may be used to enhance imaging of the blood pool. See, e.g., WO 96/23526, herein incorporated by reference in its entirety. Such diagnostic imaging contrast agents may comprise an image-enhancing moiety, a plasma protein binding moiety and a blood half-life extending moiety and exhibit improved blood retention. Although a number of methods using such contrast agents have been described, prior to this application it was not known if normal sexual function or sexual dysfunction could be measured with such types of agents.
The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Washington D.C., American Psychiatric Association, 1996 (DSM-IV, herein incorporated by reference) describes a number of sexual dysfunctions. These include sexual desire disorders such as hypoactive sexual desire disorder and sexual aversion disorder; sexual arousal disorders such as female sexual arousal disorder and male erectile disorder; orgasmic disorders such as female orgasmic disorder (formerly, inhibited female orgasm), male orgasmic disorder (formerly, inhibited male orgasm), and premature ejaculation, dyspareunia, vaginismus and sexual dysfunction not otherwise specified. The DSM-IV describes several subtypes that apply to primary sexual dysfunctions including lifelong type, acquired type, generalized type, situational type, and sexual dysfunction due to psychological factors or due to combined factors. Sexual dysfunction may also be due to general medical condition or may be substance induced, such as by alcohol, antidepressants and antihypertensives.
A number of compounds have been described to treat sexual dysfunction. For instance, Viagra(trademark) (sildenafil citrate, Pfizer, Inc.) has been used to treat male erectile disorder. Physiologically, sexual stimulation causes local release of nitric oxide (NO) in the corpus cavernosum. NO then activates the enzyme guanylate cyclase, which results in increased levels of cGMP, producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil citrate enhances the effect of NO by specifically inhibiting PDE5, which is responsible for degradation of cGMP in the corpus cavernosum.
Female sexual arousal disorder is a poorly understood condition for which there is no reliable diagnostic test. The underlying pathophysiology of this condition is thought to include an inadequate vascular arousal response to sexual stimulation. Vaginal photoplethysmography is the most widely reported method for assessing the vascular component of the arousal response to sexual stimulation (by measuring a change in vaginal pulse amplitude). However, vaginal photoplethysmography has the disadvantage of not providing an absolute measure of either vaginal blood volume or blood flow because all changes are observed without a quantifiable reference baseline. Furthermore, photoplethysmography results are highly variable and depend on exact placement of the probe, among other parameters. Thus, there remains a need to develop better methods and techniques for measuring blood flow in sexual response, preferably female sexual response, and, more particularly, in female sexual arousal disorders.
In one embodiment, the instant invention provides a method for contrast-enhanced diagnostic imaging of normal sexual function or sexual dysfunction. In a preferred embodiment, MRI, ultrasound, computed X-ray tomography (CT), or optical imaging is used to image sexual dysfunction. In a more preferred embodiment, the sexual dysfunction is a female sexual arousal disorder.
In another embodiment, the instant invention provides a method for measuring the therapeutic effect of a compound on sexual dysfunction. In a preferred embodiment, MRI or optical imaging is used to measure the effects of the therapeutic compounds. In another preferred embodiment, the sexual dysfunction treated is female sexual arousal disorder. In an even more preferred embodiment, the compound tested is sildenafil citrate (Viagra(trademark)).
In another embodiment, the instant invention provides a method for screening for potential therapeutic compounds for efficacy in the treatment of sexual dysfunction. In a preferred embodiment, the compounds are screened for treating female sexual arousal disorder. In another preferred embodiment, MRI or optical imaging is used to screen the compounds.